The most appropriate conventional DMARD to combine with different advanced therapies in rheumatoid arthritis: a systematic literature review with meta-analysis.

Decarriere, Guillaume; Barnetche, Thomas; Combe, Bernard; Gaujoux-Viala, Cécile; Lukas, Cédric; Morel, Jacques; Daien, Claire

BACKGROUND In rheumatoid arthritis, the association between advanced therapies (including biologics DMARDs and targeted synthetic DMARDs) and MTX is recommended by international societies. When MTX cannot be used, other conventional synthetic DMARDs (csDMARDs) can be proposed. We aimed to compare the safety and efficacy of MTX and non-MTX csDMARDs in combination with advanced therapies. METHODS We systematically searched the literature for studies comparing the effectiveness, retention rate and safety of MTX versus non-MTX csDMARDs (leflunomide or others) in combination with tumor necrosis factor inhibitors (TNFi), abatacept, rituximab, tocilizumab, and JAK inhibitors (JAKi). Meta-analysis was performed with RevMan using an inverse variance approach with fixed or random effects models. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated. RESULTS The literature search revealed 3842 articles; 41 studies were included for the systematic literature review and 21 for the meta-analysis: 13 were of TNFi, 3 of abatacept, 5 of rituximab. For TNFi, EULAR response at 6 months was lower for patients receiving non-MTX csDMARDs than MTX (RR=0.93 [95% CI 0.87;1.0], p=0.04, n=3843, I2 =28%), with lower retention rate at 12 months. For abatacept, effectiveness and safety were similar between the 2 groups. For rituximab, good EULAR response was higher with leflunomide than MTX (RR=1.38 [95% CI 1.13;1.68], p=0.001, n=2078, I2 =0%), with similar adverse event rates. Meta-analysis for tocilizumab or JAKi could not be performed. CONCLUSION The different csDMARDs seem safe and efficient to combine with advanced therapies in RA patients. Although MTX seems slightly superior to other csDMARDs in combination with TNFi, leflunomide might be superior to MTX in combination with rituximab.